Downloaded from http://bmjopen.bmj.com/ on June 16, 2017 - Published by group.bmj.com
PEER REVIEW HISTORY
BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to
complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and
are provided with free text boxes to elaborate on their assessment. These free text comments are
reproduced below.
ARTICLE DETAILS
TITLE (PROVISIONAL)
AUTHORS
Glucose intolerance associated with hypoxia in people living at high
altitudes in the Tibetan highland
Okumiya, Kiyohito; Sakamoto, Ryota; Ishimoto, Yasuko; Kimura,
Yumi; Fukutomi, Eriko; Ishikawa, Motonao; Suwa, Kuniaki; Imai,
Hissei; Chen, Wenling; Kato, Emiko; Nakatsuka, Masahiro;
Kasahara, Yoriko; Fujisawa, Michiko; Wada, Taizo; Wang, Hongxin;
Dai, Qingxiang; Xu, Huining; Qiao, Haisheng; Ge, Ri-Li; Norboo,
Tsering; Tsering, Norboo; Kosaka, Yasuyuki; Mitsuhiro, Nose;
Yamaguchi, Takayoshi; Tsukihara, Toshihiro; Ando, Kazuo;
Inamura, Tetsuya; Takeda, Shinya; Ishine, Masayuki; Otsuka,
Kuniaki; Matsubayashi, Kozo
VERSION 1 - REVIEW
REVIEWER
REVIEW RETURNED
Martin Burtscher
University of Innsbruck, Austria
08-Sep-2015
GENERAL COMMENTS
Review of the manuscript “Glucose intolerance associated with
hypoxia in people living at high altitudes in the Tibetan highland”
This observational study aimed at evaluating the association
between glucose intolerance and hypoxemia related to living at high
altitudes (2900–4900 m) in the Tibetan highlands.
A total of 1258 subjects aged between 40 and 87 years living in rural
and urban areas or being nomads were studied. The authors
concluded that socioeconomic factors, hypoxemia, and the effects of
altitudes over 3500 m may play a major role in the high prevalence
of glucose intolerance in Tibetan highlanders who might be
vulnerable to glucose intolerance. In addition, the authors found a
relatively high prevalence of polycythemia.
In general this is a nice epidemiological study reporting interesting
data on a relatively large and extraordinary study population.
However, the manuscript is a bit confusing and sometimes hard to
read. The paper should be largely restructured, e.g. subheadings
like “study population”, “measurements”, “statistics” should be used
for the methods section. Also the results and discussion section
should be presented clearer and more concise and a more extended
limitation section should be added. Proof-reading by an English
native speaker is urgently recommended. In addition, there are
several concerns that should be addressed before a final
recommendation can be made:
1. It is not clear from the introduction why Tibetan highlanders
should really have an extraordinary vulnerability to diabetes. Please,
explain.
2. A major problem may arise from a potential selection bias. How
Downloaded from http://bmjopen.bmj.com/ on June 16, 2017 - Published by group.bmj.com
can you assure that this is not the case?
3. Important confounding may be due to lacking information on
smoking, physical activity, nutrition, alcohol drinking, etc. Do you
have such data?
4. Please provide sample sizes when describing the population of
the various areas.
5. It is not entirely clear when you performed blood glucose
measurements; in the morning hours, after overnight fasting,
and/or??
6. Both the result and the discussion section could be shortened.
7. The interpretation of the results is not totally convincing. For
example, the prevalence of hyperglycemia and DM at least with
regard to the OGTT (table 6 and table 7) do not differ between
altitudes.
8. Is hypoxemia cause or effect?
9. There is in fact a relatively high prevalence of polycythemia. What
about the prevalence of chronic mountain sickness?
10. Could you also report on the prevalence of metabolic syndrome?
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Don McClain
Wake Forest University School of Medicine
23-Sep-2015
In this paper, the authors have examined glycemic indices (fasting
and challenged glucose, HbA1c) in individuals in Tibet, China, and
India living at various altitudes. At modest altitudes, it has been
published that altitude actually protects from diabetes, but these
data show that higher latitudes are associated with worsened
glucose tolerance. There is a major concern, however:
1. The two populations with the most robust differences as a function
of altitude are the urban dwellers (Table 5), but that is a comparison
of Ladakhis and mixed Han and Tibetan Chinese, and furthermore
the prevalence of overweight is much higher in that higher altitude
group. The most homogeneous comparison is probably the nomads
(middle section in Table 5), and they show the least change in
glycemia as a function of altitude, with only fasting hyperglycemia
being significant as altitude increases. So are there perhaps issued
of ethnicity that interfere with the simple effects of altitude?
As minor concerns, the manuscript has multiple phrasings that are
awkward English, so the entire manuscript needs to be carefully
edited by a native speaker of English.
VERSION 1 – AUTHOR RESPONSE
Respond to the comments by the reviewer 1
Thank you very much! I revised the manuscript according to your precise comments.
Please state any competing interests or state ‘None declared’:
[Reply]
I described ‘None declared’
Please leave your comments for the authors below
Review of the manuscript “Glucose intolerance associated with hypoxia in people living at high
Downloaded from http://bmjopen.bmj.com/ on June 16, 2017 - Published by group.bmj.com
altitudes in the Tibetan highland”
This observational study aimed at evaluating the association between glucose intolerance and
hypoxemia related to living at high altitudes (2900–4900 m) in the Tibetan highlands.
A total of 1258 subjects aged between 40 and 87 years living in rural and urban areas or being
nomads were studied. The authors concluded that socioeconomic factors, hypoxemia, and the effects
of altitudes over 3500 m may play a major role in the high prevalence of glucose intolerance in
Tibetan highlanders who might be vulnerable to glucose intolerance. In addition, the authors found a
relatively high prevalence of polycythemia.
In general this is a nice epidemiological study reporting interesting data on a relatively large and
extraordinary study population. However, the manuscript is a bit confusing and sometimes hard to
read. The paper should be largely restructured, e.g. subheadings like “study population”,
“measurements”, “statistics” should be used for the methods section. Also the results and discussion
section should be presented clearer and more concise and a more extended limitation section should
be added. Proof-reading by an English native speaker is urgently recommended. In addition, there are
several concerns that should be addressed before a final recommendation can be made:
[Reply]
Subheadings of “study population”, “measurements”, “statistics” were used for the methods section.
Proof-reading by an English native speaker was carried out.
1. It is not clear from the introduction why Tibetan highlanders should really have an extraordinary
vulnerability to diabetes. Please, explain.
[Reply]
The following sentence was added in the introduction.
This hypothesis is based both on the current accelerated and modernized lifestyle change occurring
to middle-aged and elderly highlanders coming from a traditional childhood lifestyle, and on the high
prevalence of polycythemia in elderly Tibetan highlanders in contrast with younger Tibetans.
2. A major problem may arise from a potential selection bias. How can you assure that this is not the
case?
[Reply]
In order to clarify the association of glucose intolerance with hypoxia exactly, homogeneous people
with the same ethnicity and lifestyle should be compared among different altitudes. To minimize
selection bias in this aim, the separate analysis among the three livelihood of farmer, nomad, and
urban dweller was carried out. The homogeneous comparison could be perfectly carried out in
Ladakhi farmers between 2500–3499 m and 3500–4499 m in Domkhar. The homogeneous
comparison could be almost carried out in Tibetan nomads among 2500–3499 m, 3500–4499 m and
4500+ in Qinghai/ Changthan, and Ladakhi nomads between 3500–4499 m and 4500+ m in
Changthang. In the comparison of urban dwellers between Leh town (2500–3499 m, Tibetan and
Ladakhi) and Yushu (3500–4499 m, Tibetan), prevalence of obesity was higher in the latter by the
more development of modernized lifestyle. To adjust the effect of the lifestyle and ethnicity, multiple
logistic regression analysis was used with the other confounding factors and the association of fasting
hyperglycemia with higher altitude >3500 m was shown except for the separate analysis of urban
dwellers (Supplementary Table 2).
The following sentence was added in “ Strength and Limitation”.
Finally, a study strength was that farmers and nomads were analyzed in different altitudes as almost
homogeneous subjects.
Downloaded from http://bmjopen.bmj.com/ on June 16, 2017 - Published by group.bmj.com
Another limitation is that urban dwellers were analyzed in different altitudes who had changed to a
modernized lifestyle, which was not homogeneous. But multiple logistic regression analysis was used
for adjusting lifestyle and other confounding factors.
Supplementary Table 2 was added and the following sentences were added in Results in association
with selection bias.
The effect of livelihood or ethnicity to the association between altitudes and fasting HG were analyzed
and shown in Supplementary Table 2. In models 1–3, multivariate analyses were carried out
separately in each livelihood of farmer, nomad and urban dweller. In farmers and nomads, higher
altitude had significantly higher OR for fasting HG compared with lower altitude, but not in urban
dwellers after adjustment with other confounding factors. In models 4 and 5, multivariate analysis was
carried out separately in each ethnic group, Tibetan and Ladakhi. Higher altitude had significantly
greater OR compared with lower altitude in both groups. The OR was higher in Ladakhi (2.53 vs 1.69)
than in Tibetan. In models 6 and 7, multivariate analysis was carried out in all subjects and higher
altitude had significantly greater OR compared with lower altitude independently of livelihood and
ethnicity (Supplementary Table 2).
The following sentence was added in Discussion.
The association of high altitude >3500 m with fasting HG was shown even after adjustment of the
effects of both lifestyle and ethnicity in all subjects, and also in a separate analysis of farmers and
nomads, but not in urban dwellers.
3. Important confounding may be due to lacking information on smoking, physical activity, nutrition,
alcohol drinking, etc. Do you have such data?
[Reply]
Analysis of smoking and alcohol drinking was mentioned in the revised manuscript.
The following sentence was added in the section of Measurements.
The interviewers asked participants whether they currently or previously smoked or currently drank
alcohol.
The following sentence was added in Results.
The prevalence of current or past smokers was 4.7% (males 9.4% and females 1.1%). The
prevalence of current alcohol drinkers was 25.4% (males 35.7% and females 17.6%).
The following sentence was also added in Results.
Neither smoking nor drinking alcohol was associated with glucose intolerance.
Physical activities were asked by interviewers from 875 subjects. The prevalence of DM (Fasting
DM)/IHG (Fasting IHG); 5.2% (3.4%)/28.8% (14.9%) were lower in people who work in farming on 5
or more days per week compared with people who work on 4 or less days per week; 11.3%
(8.7%)/40.4% (21.9%), P=0.0009 (P=0.0009)/P=0.0004 (P=0.0077) (Student’s t-test). In logistic
regression models adjusted with the same confounding factors as Table 7, physical activities as an
independent variable was significantly associated with Fasting DM as dependent variable. More
physical active workers had odds ratio of 0.41(95%CI; 0.17 to 0.97) (P=0.0435) for Fasting DM
compared with lower physical active workers. The associations of other independent variables with
glucose intolerance were not influenced by adding physical activities to the models.
As there was the information of physical activities in the limited subjects, the need of consideration of
physical activities was described to “Limitation of the study”.
In this report the condition of nutrition and physical activities was evaluated by BMI and dyslipidemia.
The survey of nutrition was carried out examining the variety of nutrition and calory of food intake. The
analysis will be reported in another paper.
Downloaded from http://bmjopen.bmj.com/ on June 16, 2017 - Published by group.bmj.com
[Reply]
The following sentence was added in “Limitation”.
The study did not investigate whether nutrition and physical activities were confounding factors to
glucose intolerance, but measuring BMI and dyslipidemia may reflect those effects.
4. Please provide sample sizes when describing the population of the various areas.
[Reply]
The following sentences were added in each area in Study population.
Eighty-six agreed to take part.
and 41 Tibetan nomads agreed.
and 324 of the urban Tibetan residents agreed to participate.
and 295 Ladakhi farmers agreed to volunteer as participants in the survey.
and 308 of these urban residents (266 Tibetans and 42 Ladakhis) agreed to participate in the survey.
and 204 nomads (78 Tibetans and 126 Ladakhis) voluntarily agreed to participate.
5. It is not entirely clear when you performed blood glucose measurements; in the morning hours,
after overnight fasting, and/or??
[Reply]
The sentence in Measurements were revised as following.
Overnight fasting venous samples were collected in the morning from all participants.
6. Both the result and the discussion section could be shortened.
[Reply]
The two following sections were omitted.
What is already known about this topic
There is an inverse association between diabetes and altitude lower than 3500 m in lowlanders and
Tibetans, but no findings for altitudes over 3500 m have been reported.
Glucose intolerance is increased in high altitude dwellers by a change toward an urbanized lifestyle.
However, whether glucose intolerance is increased by hypoxia is unknown.
What this study adds
A high altitude over 3500 m is associated with an increase in fasting hyperglycemia and diabetes.
There are close associations between hypoxemia and glucose intolerance after adjusting for
confounding factors related to lifestyle changes in middle-aged and older-aged people at high altitude.
P values were omitted in the result section.
The following sentence in Discussion was omitted.
Lifestyle-related health changes were caused by socioeconomic changes. There was a higher
prevalence of overweight and dyslipidemia in urban-dwelling people compared with nomad or
farmers, more than that reported in previous studies of highlanders. These lifestyle-related health
factors were closely associated with a high prevalence of glucose intolerance in highlanders.
The following sentence in Discussion was omitted.
This higher prevalence of glucose intolerance was also found with an elevation of altitude and an
increase in hypoxemia in separate analysis of farmers, nomads, and urban dwellers.
The following sentence in Discussion was revised shortly.
These positive effects of dwelling at a higher altitude were more distinct when glucose intolerance
was defined by FBS and the entire population was analyzed by multivariate analysis after adjustment
Downloaded from http://bmjopen.bmj.com/ on June 16, 2017 - Published by group.bmj.com
for all lifestyle-related health factors.
The following sentence in Discussion was omitted.
The prevalence of high HbAlc >6.0/6.5% in fasting glucose intolerance in our result were also much
lower (36.6/14.6 % in FIHG and 59.6/35.1% in FDM) compared with those in Tosa Town (51.3/22.8%
in FIHG and 82.4/55.8% in FDM). While the prevalence of high HbAlc >6.0/6.5% in glucose
intolerance (OGTT) were not so lower (34.4/7.1 in IHG and 61.0/35.1% in DM) compared with those
in Tosa Town (32.2/8.2% in IHG and 73.5/42.2% in DM).
The following sentence in Discussion was revised shortly.
We propose the following two hypotheses for the mechanism of the strong associations among
polycythemia, hypoxemia, and glucose intolerance after adjustment with other confounding factors.
7. The interpretation of the results is not totally convincing. For example, the prevalence of
hyperglycemia and DM at least with regard to the OGTT (table 6 and table 7) do not differ between
altitudes.
[Reply]
The sentences in Results were revised as followings.
Altitude level of 3500–4499 m was closely associated with all models, while the highest level of ≥4500
m was associated with Fasting HG and Fasting DM, but not with HG or DM.
Classifying the altitude levels into two groups, 2500–3499 m and ≥3500 m, and using multiple logistic
regression analysis, the ≥3500 m altitude level was also closely associated with Fasting HG (OR =
2.19, CI: 1.53–3.12, P <0.0001) and Fasting DM (OR = 1.94, CI: 1.06–3.55, P = 0.0305), but not with
HG or DM.
8. Is hypoxemia cause or effect?
[Reply]
By our results and previous reports, hypoxemia is the effect of high-altitude, aging and obesity.
Hypoxemia is considered as the cause of glucose intolerance (Hypothesis-1) and also considered as
the effect of glucose intolerance (Hypothesis-2). Hypoxemia is considered as the cause of
polycythemia (Hypothesis-2) and also considered as the effect of polycythemia (Hypothesis-1) as
mentioned in Discussion (Figure).
9. There is in fact a relatively high prevalence of polycythemia. What about the prevalence of chronic
mountain sickness?
[Reply]
The prevalence of chronic mountain sickness was 11.6% (mild; 9.2%, moderate; 1.9%, severe; 0.4%)
in the all subjects by the definition of the Qinghai CMS Score (High Altitude Medicine and Biology
2005; 6-2: 147-157.) and this will be reported in another paper.
10. Could you also report on the prevalence of metabolic syndrome?
[Reply]
The prevalence of metabolic syndrome was 26.5% in the all subjects (ATP-III for Asian
and ADA criterion) and this will be reported in another paper.
Thank you very much.
Downloaded from http://bmjopen.bmj.com/ on June 16, 2017 - Published by group.bmj.com
Respond to the comments by the reviewer 2
Thank you very much! I revised the manuscript according to your precise comments.
Please state any competing interests or state ‘None declared’:
[Reply]
I described ‘None declared’
In this paper, the authors have examined glycemic indices (fasting and challenged glucose, HbA1c) in
individuals in Tibet, China, and India living at various altitudes. At modest altitudes, it has been
published that altitude actually protects from diabetes, but these data show that higher latitudes are
associated with worsened glucose tolerance. There is a major concern, however:
1. The two populations with the most robust differences as a function of altitude are the urban
dwellers (Table 5), but that is a comparison of Ladakhis and mixed Han and Tibetan Chinese, and
furthermore the prevalence of overweight is much higher in that higher altitude group. The most
homogeneous comparison is probably the nomads (middle section in Table 5), and they show the
least change in glycemia as a function of altitude, with only fasting hyperglycemia being significant as
altitude increases. So are there perhaps issued of ethnicity that interfere with the simple effects of
altitude?
As minor concerns, the manuscript has multiple phrasings that are awkward English, so the entire
manuscript needs to be carefully edited by a native speaker of English.
[Reply]
In order to clarify the association of glucose intolerance with hypoxia exactly, homogeneous people
with the same ethnicity and lifestyle should be compared among different altitudes. To minimize
selection bias in this aim, the separate analysis among the three livelihood of farmer, nomad, and
urban dweller was carried out. The homogeneous comparison could be perfectly carried out in
Ladakhi farmers between 2500–3499 m and 3500–4499 m in Domkhar. The homogeneous
comparison could be almost carried out in Tibetan nomads among 2500–3499 m, 3500–4499 m and
4500+ in Qinghai/ Changthang, and Ladakhi nomads between 3500–4499 m and 4500+ m in
Changthang. In the comparison of urban dwellers between Leh town (2500–3499 m, Tibetan and
Ladakhi) and Yushu (3500–4499 m, Tibetan), prevalence of obesity was higher in the latter by the
more development of modernized lifestyle. To adjust the effect of the lifestyle and ethnicity, multiple
logistic regression analysis was used with the other confounding factors and the association of fasting
hyperglycemia with higher altitude >3500 m was shown except for the separate analysis of urban
dwellers (Supplementary Table 2).
Supplementary Table 2 was added and the following sentences were added in Results
The effect of livelihood or ethnicity to the association between altitudes and fasting HG were analyzed
and shown in Supplementary Table 2. In models 1–3, multivariate analyses were carried out
separately in each livelihood of farmer, nomad and urban dweller. In farmers and nomads, higher
altitude had significantly higher OR for fasting HG compared with lower altitude, but not in urban
dwellers after adjustment with other confounding factors. In models 4 and 5, multivariate analysis was
carried out separately in each ethnic group, Tibetan and Ladakhi. Higher altitude had significantly
greater OR compared with lower altitude in both groups. The OR was higher in Ladakhi (2.53 vs 1.69)
than in Tibetan. In models 6 and 7, multivariate analysis was carried out in all subjects and higher
altitude had significantly greater OR compared with lower altitude independently of livelihood and
ethnicity (Supplementary Table 2).
The following sentence was added in Discussion.
The association of high altitude >3500 m with fasting HG was shown even after adjustment of the
effects of both lifestyle and ethnicity in all subjects, and also in a separate analysis of farmers and
Downloaded from http://bmjopen.bmj.com/ on June 16, 2017 - Published by group.bmj.com
nomads, but not in urban dwellers.
The following sentence was added in “ Strength and Limitation”.
Finally, a study strength was that farmers and nomads were analyzed in different altitudes as almost
homogeneous subjects.
Another limitation is that urban dwellers were analyzed in different altitudes who had changed to a
modernized lifestyle, which was not homogeneous. But multiple logistic regression analysis was used
for adjusting lifestyle and other confounding factors.
Thank you very much.
VERSION 2 – REVIEW
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Martin Burtscher
University of Innsbruck
Austria
01-Dec-2015
The authors responded adequately to all my concerns.
I do not have further comments.
Thank you!
REVIEWER
REVIEW RETURNED
Don McClain
Wake Forest University School of Medicine
Winston-Salem, NC, USA
17-Nov-2015
GENERAL COMMENTS
I am satisfied with the response to the review.
Downloaded from http://bmjopen.bmj.com/ on June 16, 2017 - Published by group.bmj.com
Glucose intolerance associated with hypoxia
in people living at high altitudes in the
Tibetan highland
Kiyohito Okumiya, Ryota Sakamoto, Yasuko Ishimoto, Yumi Kimura,
Eriko Fukutomi, Motonao Ishikawa, Kuniaki Suwa, Hissei Imai, Wenling
Chen, Emiko Kato, Masahiro Nakatsuka, Yoriko Kasahara, Michiko
Fujisawa, Taizo Wada, Hongxin Wang, Qingxiang Dai, Huining Xu,
Haisheng Qiao, Ri-Li Ge, Tsering Norboo, Norboo Tsering, Yasuyuki
Kosaka, Mitsuhiro Nose, Takayoshi Yamaguchi, Toshihiro Tsukihara,
Kazuo Ando, Tetsuya Inamura, Shinya Takeda, Masayuki Ishine, Kuniaki
Otsuka and Kozo Matsubayashi
BMJ Open 2016 6:
doi: 10.1136/bmjopen-2015-009728
Updated information and services can be found at:
http://bmjopen.bmj.com/content/6/2/e009728
These include:
References
This article cites 68 articles, 15 of which you can access for free at:
http://bmjopen.bmj.com/content/6/2/e009728#BIBL
Open Access
This is an Open Access article distributed in accordance with the Creative
Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work
non-commercially, and license their derivative works on different terms,
provided the original work is properly cited and the use is
non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Email alerting
service
Receive free email alerts when new articles cite this article. Sign up in the
box at the top right corner of the online article.
Topic
Collections
Articles on similar topics can be found in the following collections
Diabetes and Endocrinology (385)
Epidemiology (2038)
Notes
To request permissions go to:
http://group.bmj.com/group/rights-licensing/permissions
To order reprints go to:
http://journals.bmj.com/cgi/reprintform
To subscribe to BMJ go to:
http://group.bmj.com/subscribe/